Vitamin D.sub.3 is a derivative of provitamin D.sub.3 (7-dehydrocholesterol), the immediate biological precursor of cholesterol. With adequate exposure to sunlight, dietary supplements are not normally required. Holick et al. in Braunwald et al., Harrison's Principles of Internal Medicine, 11th ed. McGraw-Hill (1987), pp. 1857-69. However, not all individuals are exposed to the adequate levels of sunlight, especially in the winter.
When skin is exposed to sunlight or artificial sources of ultraviolet (UV) radiation, the UV radiation penetrates the epidermis and causes a variety of biochemical reactions. Included in these reactions is the transformation of provitamin D.sub.3 to previtamin D.sub.3. The solar electromagnetic energy having wavelengths between 290 and 315 nm is absorbed by provitamin D.sub.3 resulting in its fragmentation to previtamin D.sub.3. Although previtamin D.sub.3 is biologically inert, it is thermally labile and spontaneously undergoes a temperature-dependent rearrangement to form the thermally stable vitamin D.sub.3. After biosynthesis, vitamin D.sub.3 is translocated from the epidermis into the circulation via a vitamin-D binding protein. Holick et al., Science 211:590-593 (1981); Holick et al. in Braunwald et al., Harrison's Principles of Internal Medicine, 11th ed., McGraw-Hill (1987), pp. 1857-69.
Factors that are frequently considered as affecting the cutaneous synthesis of vitamin D.sub.3 include age, altitude, geographical location, time of day, seasonal changes and area of exposure to sunlight. Common to most of these factors is the availability of the requisite amount of ultraviolet radiation with energies between 290 and 315 nm which is necessary to convert provitamin D.sub.3 to previtamin D.sub.3. MacLaughlin et al., Science 216:1001-1003 (1982).
The availability of a vitamin D precursor (provitamin D.sub.3) in the skin and its photo-induced transformation to previtamin D.sub.3 and then to vitamin D.sub.3 is an efficient physiological source of and mechanism for the replenishment of vitamin D.sub.3. However, during the winter in northern latitudes, sunlight does not contain enough high energy ultraviolet radiation to convert provitamin D.sub.3 (7-dehydrocholesterol) in human skin to previtamin D.sub.3. As a result, individuals in these latitudes cannot make vitamin D.sub.3 in their skin, even when they are exposed to sunlight. Webb, Kline and Holick, J. Clin. Endocrin. Met. 67:373-378 (1988). The lack of adequate exposure to ultraviolet radiation gives rise to the possibility of serious vitamin D deficiency, a breakdown in blood calcium regulation with concomitant hypocalcemia and bone calcium wasting.
The availability of the vitamin D precursor in the skin and its photo-induced transformation to previtamin D.sub.3, and then to vitamin D.sub.3, is an efficient physiological source of, and mechanism for the replenishment of vitamin D.sub.3. Previously, it was thought that the only method of producing previtamin D.sub.3 in the skin was to transform provitamin D.sub.3. This transformation requires sunlight or artificial UV light in the region of 290-315 nm. Therefore, in areas where the available light energy is below this range (wavelengths greater than 316 nm), the transformation does not occur to any significant extent. Kobayashi et al., J. Nutr. Sci. Vitaminol. 19:123 (1973).
It has been disclosed (Holick, M., Transactions of the Association of American Physicians, 42:54-63 (1979); Molecular Endocrinology; MacIntyre and Szelke, eds.; Elsevier/North Holland Biomedical Press (1979), pp.301-308) that the topical application of hydroxylated metabolites of provitamin D compounds to the skin combined with U.V. phototherapy is a method for the sustained administration of vitamin D metabolites to patients who suffer vitamin D metabolic disorders. When the hydroxylated provitamins are applied and irradiated with ultraviolet radiation, they convert to hydroxylated previtamins which then thermally isomerize to the hydroxylated vitamin D. This work is also disclosed in Holick et al., New England Journal of Medicine 301:349-354 (1980) and U.S. Pat. No. 4,310,511 (Jan. 12, 1982).
Hungarian Patent No. 102,939 discloses cosmetic creams containing vitamin D precursors (such as ergosterol) which, when irradiated with ultraviolet rays, are transformed into vitamin D.
MacLaughlin et al., Science 216:1001-1003 (1982), disclose the synthesis of previtamin D.sub.3 from provitamin D.sub.3 in human skin and in an organic solvent after exposure to narrow-band radiation or simulated solar radiation. When human skin or an organic solvent containing provitamin D.sub.3 were exposed to 295 nm radiation, up to 65% of the provitamin D.sub.3 was converted to previtamin D.sub.3. The authors further disclose that the optimum wavelength for the production of previtamin D.sub.3 is between 295 nm and 300 nm.
Dauben et al., J. Am. Chem. Soc. 104:5780-5781 (1982); J. Am. Chem. Soc. 104:355-356 (1982), disclose the effect of wavelength on the photochemistry of provitamin D.sub.3 and the effect of wavelength on the production of previtamin D.sub.3. The authors found that when provitamin D.sub.3 is exposed to light in the range of 254 nm, it is converted to a variety of photoproducts, the major portion being about 75% tachysterol. This mixture was then exposed to either 300 nm of light, broad-band 350 nm light or 355 nm light to give a build up of previtamin D.sub.3. Dauben et al. conclude that if provitamin D.sub.3 is first irradiated at 0.degree. C. with 254 nm light to give a quasi photostationary state of provitamin D.sub.3, previtamin D.sub.3, tachysterol and lumisterol, and the mixture is thereafter irradiated (0.degree. C.) with 350 nm light, a maximum of 83% previtamin D.sub.3 is produced.
Malatesta et al., J. Amer. Chem. Soc. 103:6781-6783 (1981) , disclose the effects of different UV wavelengths on the relative quantities of photoproducts produced from provitamin D.sub.3.
Holick et al. disclose that the photochemical convers ion of previtamin D.sub.3 to lumisterol and tachysterol is the major factor that prevents vitamin D.sub.3 intoxication after a single prolonged exposure to the sun. Holick et al., Science 211:590-592 (1981). The corollary to this finding is that lumisterol and tachysterol are two biologically inert products thought to be sloughed off the skin during the natural turnover of the epidermal cells.
Provitamin D.sub.2 (ergosterol) is the precursor of vitamin D.sub.2. Vitamin D.sub.2 is one of the major forms of vitamin D that is used to fortify foods such as milk and multivitamins.